Page 348 - Read Online
P. 348
Page 6 of 12 Sharma et al. Neuroimmunol Neuroinflammation 2018;5:43 I http://dx.doi.org/10.20517/2347-8659.2018.51
Table 2. List of clinical trials investigating the efficacy of chimeric antigen receptor T-cell therapy across multiple antigens
expressed in brain cancer
Antigen Disease Intervention/treatment Identifier
MUC1 Malignant glioma Anti-MUC1 CAR-T cells in patients with malignant glioma NCT02617134
EGFRvIII, IL12Ra2, HER2, Recurrent malignant CAR T cells redirected to target tumor specific/associated antigens in NCT03423992
CD133, EphA2, GD2 glioma patients with recurrent malignant gliomas
HER2 Pediatric CNS tumors HER2-specific CAR T cell for recurrent/refractory pediatric CNS tumors NCT03500991
EGFRvIII Malignant gliomas Anti-EGFRvIII CAR T cells in patients with malignant glioma NCT01454596
IL13Ra2 Recurrent malignant IL13Ra2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated NCT02208362
glioma CD19-expressing autologous T lymphocytes
CD133 Glioma Anti-CD133 modified CAR T cells in relapsed patients with malignant NCT02541370
glioma
HER2 GBM CMV-specific CTLs expressing CAR targeting HER2 positive recurrent NCT01109095
GBM patients
CAR: chimeric antigen receptor; CNS: central nervous system; CTLs: cytotoxic T lymphocytes
of peripherally infused EGFRvIII directed CAR-Ts. In their phase-I open label study, all 10 patients had
an unmethylated MGMT promoter, known to be a poor prognostic factor. The median level of EGFRvIII
expression was 71% (6%-96%). Importantly, there were no dose-limiting toxicities, and CAR-T therapy was
not associated with EGFR-directed toxicity, systemic toxicity (CRS - see below) or neurotoxicity - signs and
symptoms observed with CD-19- CAR-T cells. Median overall survival (OS) was 251 days (8 months) with
[29]
one subject alive without further therapy 18 months after a single infusion of CART-EGFRvIII .
Other tumor biomarkers expressed by GBM are being tested in several institutions across the world. Yang
and colleagues at Hefei Binhu Hospital are testing a modified CAR-T cell redirected to target MUC1 positive
tumors in patients with recurrent/relapsed malignant glioma (NCT02617134). Lin and colleagues at Xuanwu
Hospital in China are recruiting patients with recurrent malignant gliomas to test a spectrum of tumor
specific/associated antigens including EGFRvIII, IL12Ra2, HER2, CD133, EphA2 and GD2 (NCT03423992).
Rosenberg’s group from the National Cancer Institute is investigating an anti-EGFRvIII CAR in patients with
malignant glioma who are positive for EGFRvIII (NCT01454596). In a phase I clinical trial, Vitanza from
Seattle Children’s Hospital is testing a HER2-specific CAR in recurrent/refractory pediatric patients diagnosed
with CNS tumors (NCT03500991). At Baylor College of Medicine, Ahmed and colleagues developed an
autologous second-generation Cytomegalovirus (CMV)-specific CAR targeting HER2-positive GBM cells.
It is currently undergoing evaluation in a clinical trial for patients diagnosed with GBM (NCT01109095).
Chinese PLA General Hospital has deployed a phase I clinical trial investigating an anti-CD133 CAR in
[28]
relapsed patients with advanced malignancies including brain tumors (NCT02541370). Brown et al. at
the City of Hope Medical Center have developed and deployed a phase I clinical trial testing a second-
generation IL13Rα2-specific CAR in recurrent patients with malignant glioma (NCT02208362). Her group is
also testing single and combined delivery routes including intracavity, intratumoral and intraventricular in
order to identify the optimal route for T-cell infusion that will maximize antitumor response. These studies
are further summarized in Table 2.
SYSTEMIC AND NEUROLOGICAL TOXICITY OF CAR-T CELLS
CAR-T treatment is not without toxicities, which have been well-studied over the years for all of the different
products created and investigated in clinical trials. One of these products (JCAR015) had to be taken off the
[30]
market after the death of five patients from severe cerebral edema and herniation .
The primary toxicity that has been seen across trials and is now well-described is cytokine release syndrome
or cytokine release syndrome (CRS). This is characterized by fever, malaise, anorexia, myalgias, hypotension,
and can include multi-organ dysfunction. The mechanism continues to be explored but the release of